Natural history studies We operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that we are currently studying include non-syndromic polydactyly, Proteus syndrome, fibroadipose overgrowth syndrome, an atypical Progeria syndrome, and Lenz microphthalmia syndrome. A recent focus has been to understand the relationship of Proteus syndrome to deep vein thrombosis and pulmonary embolism. To address this we are performing a systematic evaluation of both vascular and plasma mediators of coagulation in these patients. Genotype-Phenotype studies A key objective of genetic research is to understand not only what genes are associated with what phenotypes, but to understand in detail how specific variants are correlated with specific manifestations and the severity and complications of these disorders. These studies take a great deal of time and effort to attract sufficient patients. We are currently focusing on fibroadipose overgrowth disorders and are developing a cohort of 50 patients with detailed clinical analysis coupled to mutation detection from biopsied specimens. The challenge here is greater than it is for germline (inherited) disorders because in addition to gene, variant, and genetic background, one must take into account the mosaicism level in the patient, which is clearly an important variable. We have published interim results on the first 32 such patients, the largest in the world. Therapeutic Studies The identification of the molecular etiology for Proteus syndrome and fibroadipose overgrowth and CLOVES syndrome provide an exciting new opportunity to develop therapeutic approaches to these devastating disorders. We have undertaken efforts to develop data for valid therapeutic endpoints for therapy of overgrowth disorders. We are working on two primary approaches - the first is an MRI volumetric approach in collaboration with NIH Clinical Center imaging. The second approach is a quantitative surface measurement technique. We have established a productive collaborative agreement with a pharmaceutical companies to repurpose an oncology drug for these trials. We have performed significant in vitro work (see companion Z01 on molecular studies) and have designed a phase 0 dose finding trial for this drug which will be submitted for SRC and IRB review in the fall of 2014. We have also cofounded an international consortium to test therapeutic agents in PIK3CA related overgrowth disorders with the University of Cambridge and Lyon University. This group will be launching its first trial in early 2015. Behavioral studies We have also undertaken studies to explore the behavioral aspects of these disorders. Adaptation to these conditions is a key component of quality of life for patients. To that end, we have completed interview studies to evaluate self-perception and adaptation in patients with Bardet-Biedl syndrome. This manuscript is now ready for submission. We have also developed a qualitative interview study for patients with these disorders who receive genomic testing results to gauge their interest and reactions to this testing, a key attribute that clinicians will need to consider when undertaking such analyses, whether clinical or research sequencing. Transcripts from these interviews have been coded and analyzed and will be analyzed this fall. In addition, Dr. Biesecker is a co-founder and co-director of the Elements of Morphology dysmorphology standards working group. This group is working to standardize malformation descriptions to increase the utility of clinical descriptions and journal reports. The group has recently published definitions for genital anomalies and a set of general terms used in the field. Our next project will be an expanded set of limb morphology terms to follow on our prior set of limb terms.